Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the neuronal ceroid-lipofuscinoses (NCLs) are often referred to as lysosomal storage disorders, information on brain lysosomal hydrolases in NCLs is not available. We have determined the specific activities of several acid hydrolases in postmortem brain gray matter of infantile (INCL), late infantile (LINCL), juvenile (JNCL), and adult (ANCL) forms of NCL, patients affected with other neurological disorders (ON), and normal controls. The specific activities of beta-hexosaminidase A and B were significantly high in JNCL gray matter, whereas in LINCL, the increase is significant only in beta-hexosaminidase compared to the controls. A significant increase in the activities of alpha-mannosidase, beta-glucuronidase, and acid phosphatase was also observed in LINCL and JNCL patients compared to the control values. beta-galactosidase activity was also found to be elevated in JNCL brains over the controls. In contrast, activities of beta-glucosidase and sialidase appeared to be lowered in INCL and LINCL. On the other hand, alpha-fucosidase, beta-mannosidase, and sulfatase were unaffected in NCLs brains. Thus, the present data indicate NCLs related abnormalities in some of the acid hydrolases in brain gray matter, which are primarily glycoproteins of lysosomal origin. These data in conjuction with the reported association of sphingolipid activator proteins (SAP) A and D and lysosomal glycoproteins with NCL storage bodies imply abberations in the glycoconjugate metabolism and lysosomal function.
Mol Chem Neuropathol
PMID:Brain lysosomal hydrolases in neuronal ceroid-lipofuscinoses. 897 94

The 35/50 kDa mucin-like surface glycoprotein (gp35/50) of Trypanosoma cruzi metacyclic trypomastigotes has been implicated in mammalian cell invasion. In this study we investigated whether the sialyl residues of gp35/50 are required for interaction of parasites with target cells. After treatment with bacterial neuraminidase, the metacyclic forms (G strain) remained reactive with the monoclonal antibody (mAb) 10D8 but lost their reactivity with mAb 3C9, that recognizes sialic acid-containing epitopes on gp35/50, and entered HeLa cells in significantly higher numbers as compared to untreated controls. Resialylation of gp35/50, by incubation of parasites with T. cruzi trans-sialidase and sialyl lactose, restored the reactivity with mAb 3C9 as well as the affinity for sialic acid specific lectin. Accordingly, the rate of invasion of resialylated parasites was reduced to levels similar to those observed before desialylation. Purified G strain gp35/50, desialylated by neuraminidase treatment, bound to HeLa cells more than its sialylated counterpart. The Ca2+ signaling activity, which has been associated with cell invasion, was also determined by measuring the cytosolic Ca2+ concentration ([Ca2+]i), in HeLa cells upon interaction with sonicated extracts from untreated or neuraminidase-treated parasites, or with purified gp35/50 in its sialylated or desialylated form. Consistent with the results of cell invasion assay, the desialylated parasite preparations, as well as the sialic acid free gp35/50, induced an average elevation in [Ca2+]i significantly higher than that triggered by untreated controls. None of these effects, namely the increase in infectivity and Ca2+ signaling activity, was observed with neuraminidase-treated CL strain metacyclic trypomastigotes, which express a variant form of sialic acid gp35/50 molecule that is not recognized by mAb 10D8 and apparently is not involved in target cell invasion.
Mol Biochem Parasitol 1997 Jan
PMID:Removal of sialic acid from mucin-like surface molecules of Trypanosoma cruzi metacyclic trypomastigotes enhances parasite-host cell interaction. 904 21

Incubation of human vitamin D3-binding protein (Gc protein), with a mixture of immobilized beta-galactosidase and sialidase, efficiently generated a potent macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar. Stepwise incubation of Gc protein with immobilized beta-galactosidase and sialidase, and isolation of the intermediates with immobilized lectins, revealed that either sequence of hydrolysis of Gc glycoprotein by these glycosidases yields the macrophage-activating factor, implying that Gc protein carries a trisaccharide composed of N-acetylgalactosamine and dibranched galactose and sialic acid termini. A 3 hr incubation of mouse peritoneal macrophages with picomolar amounts of the enzymatically generated macrophage-activating factor (GcMAF) resulted in a greatly enhanced phagocytic activity. Administration of a minute amount (10-50 pg/mouse) of GcMAF resulted in a seven- to nine-fold enhanced phagocytic activity of macrophages. Injection of sheep red blood cells (SRBC) along with GcMAF into mice produced a large number of anti-SRBC antibody secreting splenic cells in 2-4 days.
Mol Immunol 1996 Oct
PMID:Structural definition of a potent macrophage activating factor derived from vitamin D3-binding protein with adjuvant activity for antibody production. 907 Jun 63

An accumulating body of evidence suggests that T. cruzi-infected host cells are recognized and destroyed by class I major histocompatibility complex (MHC) restricted CD8+ T-cells thus contributing to immune control of the infection [1-6]. However, to date, only a few amastigote proteins which could be the target of this response have been described and gene sequence information is available only for the amastins [7]. In order to identify amastigote proteins which could contribute to immune detection of infected host cells, a panel of monoclonal antibodies specific for amastigote proteins was produced and screened. Three mAbs (IIIC4, VIIC1 and IIID4) were identified which recognized amastigote surface proteins of 78, 26 and 53 kDa, respectively. Screening of an amastigote cDNA expression library with mAb IIIC4 resulted in the isolation of a 2.8 Kb clone. pSI2. The derived amino acid sequence indicates that the pSI2 clone encodes an amastigote surface protein belonging to the T. cruzi trans-sialidase super-family. Based on its preferential expression in the amastigote stage we have named this protein amastigote surface protein-1 (ASP-1). ASP-1 contains the third and fourth Asp block motifs, SxDxGxTW and the fibronectin type III-like domain, VTVxNVxLYNR, thus placing it in family II of the T. cruzi trans-sialidases [8]. ASP-1 is the first trans-sialidase family member shown to be preferentially expressed in the amastigote stage of the T. cruzi life cycle. This expression of ASP-1 on parasites in infected cells and its apparent membrane attachment by a glycosylphosphatidylinositol (GP1)-anchor makes it a prime candidate to enter the class I MHC processing and presentation pathway.
Mol Biochem Parasitol 1997 May
PMID:The identification and molecular characterization of Trypanosoma cruzi amastigote surface protein-1, a member of the trans-sialidase gene super-family. 917 63

Amastigote surface proteins of Trypanosoma cruzi are likely targets of both humoral and cell-mediated immune responses, however, few such molecules have been well studied. In this study, we have used modified RACE (rapid amplification of cDNA ends) and SOE (gene splicing by overlap extension) polymerase chain reaction strategies to clone the gene for the previously described 83 kDa amastigote surface protein of T. cruzi. Of the several clones obtained, only one clone, clone 4, was found to encode the 20 amino acid sequence originally reported by Pan and McMahon-Pratt (J Immunol 1989;143:1001-1008). The identity of the cloned gene with the 83 kDa amastigote surface protein was further confirmed by the reactivity of polyclonal antisera against the purified 83 kDa protein with the gene product expressed in E. coli. Sequence analyses revealed that this amastigote surface protein (ASP-2) has two conserved aspartic acid box motifs and the highly conserved VTVxNVxLYNR motif characteristic of bacterial and viral sialidases and the type III module of fibronectin, respectively. ASP-2 thus joins ASP-1 as a member of the amastigote surface expressed family of sialidase-like molecules having strong homology with family 2 of the sialidase/trans-sialidase gene superfamily of T. cruzi.
Mol Biochem Parasitol 1997 Sep
PMID:Molecular cloning of the gene encoding the 83 kDa amastigote surface protein and its identification as a member of the Trypanosoma cruzi sialidase superfamily. 927 75

Asparagine-linked sugar chains were quantitatively released from chimpanzee, Rhesus monkey and rat IgA proteins as oligosaccharides by hydrazinolysis, converted to radioactive oligosaccharides by reduction with NaB3H4, and separated into neutral and two acidic fractions by paper electrophoresis. The acidic oligosaccharides were converted to neutral ones by sialidase digestion, indicating that they are sialyl derivatives. However, the content of N-acetyl and N-glycolyl neuraminic acids was different among three species. The neutral and sialidase-treated acidic oligosaccharides were fractionated by Bio-Gel P-4 column chromatography in combination with linkage-specific sequential exoglycosidase digestion. Although IgA molecules from these species have mainly biantennary complex-type sugar chains, the contents of fucose and bisecting N-acetylglucosamine residues displayed marked species differences. In addition to these sugar chains, a small amount of the high mannose-type sugar chains was detected in chimpanzee and rat, but not in Rhesus monkey IgA. These results indicated that the processing of asparagine-linked sugar chains of IgA is different in each species.
Mol Immunol 1997 May
PMID:Structural differences among serum IgA proteins of chimpanzee, rhesus monkey and rat origin. 936 21

Lysosomal sialidase occurs in a multienzyme complex that also contains beta-galactosidase and cathepsin A. We previously cloned the human lysosomal sialidase cDNA and characterized mutations in human sialidosis patients. Here, we report the cloning and expression of the mouse lysosomal sialidase cDNA and gene. The 1.77 kb cDNA encodes an open reading frame of 408 amino acids which shows high homology to the human lysosomal sialidase (80%), the rat cytosolic sialidase (65%) and viral and bacterial sialidases (50-55%). The sialidase gene is approximately 4 kb long and contains six exons. The five introns range in size from 96 to 1200 bp. Northern blot analysis revealed high expression of multiple sialidase transcripts in kidney and epididymis, moderate levels in brain and spinal cord, and low levels in adrenal, heart, liver, lung and spleen. Transient expression of the cDNA clone in sialidase-deficient SM/J mouse fibroblasts and human sialidosis fibroblasts restored normal levels of sialidase activities in both cell types. Immunocytochemically expressed sialidase co-localized with a lysosomal marker, LAMP2, confirming its lysosomal nature. Since sialidase activity requires its association with beta-galactosidase and cathepsin A, the expression of mouse sialidase within human sialidosis cells underlines the structural similarity between mouse and human enzymes and suggests that the mechanism for complex formation and function is highly conserved.
Hum Mol Genet 1998 Jan
PMID:Cloning of the cDNA and gene encoding mouse lysosomal sialidase and correction of sialidase deficiency in human sialidosis and mouse SM/J fibroblasts. 938 11

Lysosomal neuraminidase (sialidase) occurs in a high molecular weight complex with the glycosidase beta-galactosidase and the serine carboxypeptidase protective protein/cathepsin A (PPCA). Association of the enzyme with PPCA is crucial for its correct targeting and lysosomal activation. In man two genetically distinct storage disorders are associated with either a primary or a secondary deficiency of lysosomal neuraminidase: sialidosis and galactosialidosis. In the mouse the naturally occurring inbred strain SM/J presents with a number of phenotypic abnormalities that have been attributed to reduced neuraminidase activity. SM/J mice were originally characterized by their altered sialylation of several lysosomal glycoproteins. This defect was linked to a single gene, neu-1 , on chromosome 17, which was mapped by linkage analysis to the H-2 locus. In addition, these mice have an altered immune response that has also been coupled to a deficiency of the Neu-1 neuraminidase. Here we report the identification in SM/J mice of a single amino acid substitution (L209I) in the Neu-1 protein which is responsible for the partial deficiency of lysosomal neuraminidase. We propose that the reduced activity is caused by the enzyme's altered affinity for its substrate, rather than a change in substrate specificity or turnover rate. The mutant enzyme is correctly compartmentalized in lysosomes and maintains the ability to associate with its activating protein, PPCA. We propose that it is this mutation that is responsible for the SM/J phenotype.
Hum Mol Genet 1998 Feb
PMID:A point mutation in the neu-1 locus causes the neuraminidase defect in the SM/J mouse. 942 40

African trypanosomes have been shown previously to undergo efficient transformation from bloodstream forms to procyclic (insect dwelling) forms in vitro by adding citrate and/or cis-aconitate to the culture medium and lowering incubation temperature to 27 degrees C. In this paper, it is shown that strain 427 monomorphic bloodstream forms of Trypanosoma brucei grown in axenic culture at 37 degrees C can be transformed to procyclic forms by simply replacing the glucose carbon source in the culture medium with glycerol. The removal of glucose from the medium results in the loss of the variant surface glycoprotein, the acquisition of cell surface procyclic acidic repetitive protein, the synthesis of procyclic-specific glycosylphosphatidylinositol precursors and the acquisition of substantial resistance to salicyl hydroxamic acid and glycerol within 72 h. A procyclic-specific cytoskeletal protein, known to be a marker of the late stage of transformation, is fully expressed by 96 h but full trans-sialidase activity appears only after 18-30 days. The transformation process described here is slower and less efficient than that previously described for monomorphic trypanosomes, using citrate and/or cis-aconitate and temperature shift as triggers. However, the separation of the transformation process from these stimuli is significant and the effects of glucose deprivation described here may reflect some of the events that occur in vivo in the tsetse fly midgut, where glucose levels are known to be very low.
Mol Biochem Parasitol 1998 Jul 01
PMID:Transformation of monomorphic Trypanosoma brucei bloodstream form trypomastigotes into procyclic forms at 37 degrees C by removing glucose from the culture medium. 971 13

Intramolecular trans-sialidase from leech (Macrobdella decora) is the first member of the sialidase superfamily found to exhibit strict specificity towards the cleavage of terminal Neu5Acalpha2-->3Gal linkage in sialoglycoconjugates. Its release of 2,7-anhydro-Neu5Ac instead of Neu5Ac indicates that it catalyzes an intramolecular trans-sialosyl reaction. Crystal structures of its complexes with an inactive substrate analogue 2-propenyl-Neu5Ac, and with the product 2,7-anhydro-Neu5Ac, have been determined to 1.8 A resolution. The boat conformation of the pyranose observed in the complexes supports the proposed enzymatic mechanism that O7 of an axial 6-glycerol group attacks the positively charged C2 of the intermediate. A generalized mechanism is proposed for the sialidase superfamily.
J Mol Biol 1999 Jan 08
PMID:The 1.8 A structures of leech intramolecular trans-sialidase complexes: evidence of its enzymatic mechanism. 987 9


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